Cited by 385DNA Repair MechanismsBlood disorders and treatmentsPARP inhibition in cancer therapy

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Human Fanconi anemia monoubiquitination pathway promotes homologous DNA repair

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Nakanishi, Koji, Yang, Yun-Gui, Pierce, Andrew J., Taniguchi, Toshiyasu, Digweed, Martin, D'Andrea, Alan D., Wang, Zhao-Qi, Jasin, Maria·2005·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0407796102PMC PMC545844

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Abstract

Fanconi anemia (FA) is a recessive disorder characterized by congenital abnormalities, progressive bone-marrow failure, and cancer susceptibility. Cells from FA patients are hypersensitive to agents that produce DNA crosslinks and, after treatment with these agents, have pronounced chromosome breakage and other cytogenetic abnormalities. Eight FANC genes have been cloned, and the encoded proteins interact in a common cellular pathway. DNA-damaging agents activate the monoubiquitination of FANCD2, resulting in its targeting to nuclear foci that also contain BRCA1 and BRCA2/FANCD1, proteins involved in homology-directed DNA repair. Given the interaction of the FANC proteins with BRCA1 and BRCA2, we tested whether cells from FA patients (groups A, G, and D2) and mouse Fanca –/– cells with a targeted mutation are impaired for this repair pathway. We find that both the upstream (FANCA and FANCG) and downstream (FANCD2) FA pathway components promote homology-directed repair of chromosomal double-strand breaks (DSBs). The FANCD2 monoubiquitination site is critical for normal levels of repair, whereas the ATM phosphorylation site is not. The defect in these cells, however, is mild, differentiating them from BRCA1 and BRCA2 mutant cells. Surprisingly, we provide evidence that these proteins, like BRCA1 but unlike BRCA2, promote a second DSB repair pathway involving homology, i.e., single-strand annealing. These results suggest an early role for the FANC proteins in homologous DSB repair pathway choice.

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Spardy, N. A. (2009) · D-Scholarship@Pitt (University of Pittsburgh) · Cited by 1
Cap a un model complet de la xarxa molecular alterada en l’anèmia de Fanconi i el càncer de mama
Sànchez, G. M. (2012) · LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas)
Additional file 3 of A functionally impaired missense variant identified in French Canadian families implicates FANCI as a candidate ovarian cancer-predisposing gene
Fierheller, C. T., Guitton-Sert, L., Alenezi, W. M., Revil, T., Oros, K. K., Gao, Y., Bédard, K., Arcand, S. L., Serruya, C., Behl, S., et al. (2021) · Figshare · doi:10.6084/m9.figshare.17124856
Additional file 2 of A functionally impaired missense variant identified in French Canadian families implicates FANCI as a candidate ovarian cancer-predisposing gene
Fierheller, C. T., Guitton-Sert, L., Alenezi, W. M., Revil, T., Oros, K. K., Gao, Y., Bédard, K., Arcand, S. L., Serruya, C., Behl, S., et al. (2021) · Figshare · doi:10.6084/m9.figshare.17124850
Additional file 4 of A functionally impaired missense variant identified in French Canadian families implicates FANCI as a candidate ovarian cancer-predisposing gene
Fierheller, C. T., Guitton-Sert, L., Alenezi, W. M., Revil, T., Oros, K. K., Gao, Y., Bédard, K., Arcand, S. L., Serruya, C., Behl, S., et al. (2021) · Figshare · doi:10.6084/m9.figshare.17124862
The FANCD2-FANCI heterodimer coordinates chromatin openness and cell cycle progression throughout DNA double-strand break repair
Joyce, C. M., Bacal, J., Chowdhury, S. P., Brown, A. N., Wang, A., Cruz, C., Bains, K., Rodriguez, Z. N., McCormick, N. J., Tzadikario, Y., et al. (2026) · Cell Reports · doi:10.1016/j.celrep.2025.116830
Expression dynamics of sex-biased development- and immune-related genes are associated with early gonadal differentiation in grass carp
Zhang, L., Li, Z., Li, S., Meng, Y., Yang, X., Li, Y., Xu, Z., Sun, Y., & Huang, Y. (2026) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2026.111201
Modulation des voies de réparation des cassures double-brin de l’ADN par ZEB1, un facteur de transcription impliqué dans l’EMT, dans le cancer du sein
Prodhomme, M. K. (2020) · theses.fr (ABES) · doi:10.70675/b91f7284z097fz467czb4d1ze6e33914f9d7
Loss of the RAD-51 isoform A redirects DNA repair and preserves genome stability in FANCD2-deficient Caenorhabditis elegans
Masullo, A., Germoglio, M., Mattossovich, R., Esposito, C., Valenti, A., & Adamo, A. (2026) · BMC Biology · doi:10.1186/s12915-026-02652-1
“These events lead to a nick in the DNA strand flanking the ICL and produce an ICL-derived double strand break (DSB) [9–11].”
HELZ-BRCA2 complex resolves R-loops to drive transcription-coupled homologous recombination
Li, W., Wu, B., Gao, B., Irvin, E. M., Ghosh, A. A., Eliaz, L., Huang, Y., Kwon, Y., Stiefel, C. M., Nguyen, T. T. N., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-75088-4
“Then, we employed the DR-GFP reporter assay to evaluate how HELZ might impact HR repair 44,45 .”

Authors: Nakanishi, K., Yang, Y.-G., Pierce, A. J., Taniguchi, T., Digweed, M., D'Andrea, A. D., Wang, Z.-Q., & Jasin, M.
Affiliations: Memorial Sloan Kettering Cancer Center (US)
Molecular Biology Program, Memorial Sloan–Kettering Cancer Center, 1275 York Avenue, New York, NY 10021; International Agency for Research on Cancer, 150 Cours Albert Thomas, 69008 Lyon, France; Department of Radiation Oncology, Dana–Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115; and Institut für Humangenetik, Charite-Campus Virchow-Klinikum, Humboldt Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
Corresponding author: Jasin, Maria
ORCID: Nakanishi, Koji
Yang, Yun-Gui
Pierce, Andrew J.
Taniguchi, Toshiyasu
Wang, Zhao-Qi
Jasin, Maria
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2005-01-13
Volume: 102
Issue: 4
Pages: 1110-1115
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.0407796102
PMC: PMC545844
OpenAlex: W2029164849
Cited by: 384
References: 42
Citations by year: 2026: 5 · 2025: 7 · 2024: 11 · 2023: 10 · 2022: 7 · 2021: 15 · 2020: 12 · 2019: 12 · 2018: 11 · 2017: 24 · 2016: 13 · 2015: 25 · 2014: 22 · 2013: 10 · 2012: 26
FWCI: 12.67
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Fanconi Anemia Research Fund
National Institutes of Health
National Cancer Institute (P01-CA94060, P01CA094060)
National Institute of General Medical Sciences (R01GM054668, GM54668)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Health Sciences › Medicine › Hematology › Blood disorders and treatments
Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
Keywords: Fanconi anemia, FANCD2 monoubiquitination, homology-directed repair, DNA double-strand break repair, single-strand annealing, BRCA1, BRCA2, FANCA, FANCG, ATM phosphorylation, DNA repair pathway choice
MeSH terms: Cell Line, DNA Repair, Humans, Nuclear Proteins, Recombination, Genetic, Ubiquitin, Fanconi Anemia Complementation Group D2 Protein

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Human Fanconi anemia monoubiquitination pathway promotes homologous DNA repair

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